Catalytic dehydration process



Patented Nov. 1 3, 1951 UNITED CATALYTIC DEHYDRATION PROCESS George Karmas, Somerville, N. J., assigno'r to ortho-Pharma'cutical Corporation, a corporation of New Jersey No Drawing Application August 9, 1947,

Serial No. 767,849

6. Claims.

This invention relates to the dehydration of tertiary allylic alcohols and more specifically this invention relates to the dehydration of tertiary allylic alcohols by their reaction with an excess of an isocyanate in the presence of a catalyst.

Heretofore catalysts have been used to promote the formation of urethanes by the reaction of an alcohol or phenol with anisocyanate, and this reaction'resulted in the formation of a stable urethane which was not readily decomposed to produce a dehydration product of the alcohol.

- In a copending application, SerialNo. 657,913, now abandoned, filed March 28, 1946', by William Oroshnik, it is disclosed-that an isocyanate and particularly phenylisocyanate may be used to dehydrate'a tertiary allylic alcohol having the following formula:

CH3 CH3 CH3 CH3 t tn Compound II in which X is and R is a hydrocarbon radical. This application'discloses that the dehydration can be accomplished without the use of a catalyst. Dehydration with an isocyanateand without a catalyst requires considerable time and the yields of dehydrated product vary but are never high; the uncatalyzed dehydrations are unpredictable because the same reactants do not always result in identical reaction products.

An object of this invention'is to dehydrate tertiary allylic alcohols by a catalyzed reaction.

Another object of this invention is to dehydrate tertiary allylic alcohols by a reaction of the said alcoholswith an isocyanate in the presence of a catalyst.

Still another object of this invention is to dehydrate tertiary allylic alcohols by a reaction of the said alcohols with at least twice their molar amount of anisocyanate in the presence of a product of a tertiary allylic alcohol is'c'onsistentIy-Obtainedingood yieldsby reacting an isocyanate in the presence ofa catalyst, with the said alcohol,'wherein an excess of isocyanate is used and preferably wherein the amount'o'f' the isocyanate used'in the reaction is equal'to'at least twice the molar amount of the tertiary'alcohol." Thisf catalytic dehydration reaction is rapidly completed'ina reproducible mariner due to the use of the catalyst in the reaction.

The following equations probably represent'the course of the reactionwhereby a tertiary allylic alcohol is dehydrated by a reaction with an isocyanate in the presence of a catalyst:

UCONHR' This intermediate reaction product represents the reaction of one molecule of isocyanate with the alcohol; the dehydration of-the alcohol is accomplished *bythereaotion ofthe'aboveur'ethanewitlia second moleculeof isocyanate. Carbon dioxide and a substituted ureaare-by-p'rod- 'u'ctsof the dehydrationreactioni The dehydratiomr'eaction' 'i's catalyzedby'anhydrous inorganic oranhydrous organic salts of heavy metals andparticularly by such salts of metals 'ofgrouplli' of the periodicdtabl'" and by anhydrous inorganic and organicferric' salts and particularly byferric halides and halides of metals of group ll. Halideswhiclihav'e'been 'foun'd espectially suitableas catalysts are ferric chloride and cadmium iodide; ferric thiocy'anate and an organic ferric salt such as the ferric salt "of 'acetylacetone have" also been foundto-give partiemarly good resultsirithe catalytic dehysamba. I

This invention has been found to have particular application in the dehydration of a divinyl carbinol of the following general formula:

CH; CH;

wherein X represents thegroups and R is a hydrocarbon radical. The preparation of compounds of the type of compound II was described in a publication in the Journal of the American Chemical Society, volume 67, page 1627 (1945). In this Publication it was disclosed by William Oroshnik that derivatives of a-ethynylp-ionol have value as intermediates in the preparation of synthetic compounds having vitamin A activity. According to this publication a compound having the following formula Compound II (Methoxy) was prepared by catalytic reduction of an acetylenic compound prepared by reacting a-ethynyl-fiionol with a Grignard reagent and an ether of a 1,4 chlorohydrin of isoprene according to the following equation:

Compound I (Methoxy) The reduction product of the acetylenic compound could be converted to a compound having vitamin A activity by a simultaneous dehydration ,and rearrangement; this was accomplished at room temperature in glacial acetic acid in the presence of a trace of p-toluene sulfonic acid. By this method a rearrangement occurred simultaneously with the dehydration and an intermediate dehydration product could not be isolated,

but compounds having Vitamin A activity were produced.

The dehydration of compounds such as Compound II may be accomplished by the practice of this invention with the production of a stable product having-five double bonds and the same configuration with respect to carbon structure as vitamin A, and thus the dehydration product then has the same number of ethylenic linkages 4 as an ester or ether of vitamin A which has the following formula:

CH3 CH;

0 -OR or O R and R is a hydrocarbon radical.

The preparation of compounds having the general formula:

CH: CH:

CH: OH: H; CH=CH-CECCHz-41=CHCH1X l H H: CH3

Compound I in which X is 3 OR or O( 2R and in which R is a hydrocarbon radical and the hydrogenation of such compounds to produce Compound II is described in a copending application, Serial No. 617,666, now abandoned, filed September 20, 1945, by William Oroshnik. The following are illustrative methods of the various methods which may be employed for producing Compounds I and II:

fl-Ionone may be reacted with calcium acetylide as described in a copending application, Serial No. 615,691, now Patent No. 2,425,201, filed September 11, 1945, by William Oroshnik, or with lithium acetylide as set forth in another copending application, Serial No. 655,607, filed March 19, 1946, by William Oroshnik, to produce aethynyl-fl-ionol. The a-ethynyl-fi-ionol produced may be reacted with a metal hydrocarbon or a hydrocarbon metal halide; the hydrocarbon metal halide used is preferably the Grignard reagent. This reaction produces, in the preferred form, a double Grignard of a-ethynyl-fi-ionol, as described in a copending application, Serial No. 657,912, now abandoned, filed March 28, 1946, by William Oroshnik. The general formula below represents the derivative of a-ethynyl-p-ionol produced by the reaction:

in which M is a metal having a valence not greater than two, Y is a halogen and R is a hydrocarbon radical; but when M is a metal having a valence of one, Y and R are non-existent; when M is a metal having a valence of two and Y is a halogen, R is non-existent; and when M is a metal having a valence of two and R is a hydrocarbon radical, Y is non-existent. In the preferred practice MY is MgBr and R is nonexistent. Among some of the illustrative compounds which may be reacted with a-GthYnYl-fiionol to produce compounds of the aforesaid formula are diethyl magnesium, ethyl magnesium bromide, methyl lithium, methyl zinc iodide,

and' 'butyl -lithium; Thesereagents mayibe-repree sented by the' general formula (R eMY; hrswhichi R is a' hydrocarbon radical, such; as: methyl:-,.

ethyl'-, benzy1--, and the. like, :c: is. an. integer: not.

greater than two, M' is a: metal havingza; valence;

not greater than two, andiY is. a halogeniiif; :zr:

isone and the :valanceof the-metaliisitwo. but. Y is-non-existent if M' is a metalhaving-avalence of one and .wis one or' if" M. a metal'havinga; valence of two and' ariSftWO'.

The compounds represented: by the: last gem eral formula shownmayrbe reacted: withzan: ester or" with" an r ether of a 1,4; ha'lohydrini of: isoprene having the following: general formular -on or -ot1a andR is a hydrocarbon radical and Z'is'a halogen.

A compound isproducedby-thi's reaction which has the following general formula:

in: which X has the: same meaning as before:-

The methods'forproducing the ester'and ether oi" the 1,4- halohydrin of isoprene' are: described in the copending applications,v Serial'N'o. 633,873; new Patent No. 2,541,091; filed December 15345, by William Oroshnik; and Serial No. 633,874, now Patent No. 2,511,870, filed December'S, 1945, by William Oroshnik.

Compound I may be. prepared in: other ways; One such method of preparing Compound I is' to react the ester or etherof the 1,4 halohydrin of isoprene with an acetylide such assodium, potassium, lithium, or calcium acetylide to produce a compound having, the formula:

in which X has the same significance as before. D

The following illustrative material illustrates the reactions leading up to and the preparation of Compound II in which X-is '-OR'-and:R-is methyl and in which X is and R is methyl.-

Preparation of the double: Grz'gnard ofa-ethyn'yl-ce-ionol One mole proportion (.218 grams) of a-ethynylc-ionol is placed in a glassfl'ask. Then about 600" grams ofanhydrous'ethyl.ether, which dissolves a-ethynyleB-ionol, are added. This solution is continuously agitated'or stirred while two mole proportions of a Grignard'reagent; and in this example 267 grams 0f"C2I-I5MgBr. dissolved in 700cc. of anhydrous ethyl ether, are gradually added. After completion of'this addition; the

To this reactionmixture containingthe double Grignardin ether solution, and which has been allowed to cool-toroom'temperature, is added one mole" proportion of' the methyl ether of'the 1,4

' chlorohydrin of" isopren'e followed by-the addition of approximately two grams of cupric-chloride as a catalyst; The; mixture is stirred under; a; reflux condenser, and heated toboiling, kept at a boiling temperature under reflux for two to four hours, then allowed'to cool to room temperature, and finally stirred for fifteenhours. At this point two layers areform'ed;

Cuprous'bromide may also be'used'to catalyze the condensation. When cupric chloride is used, a series of color changes from'dark red to'yellow occur within the. first few minutes, but when cuplrous bromide" used, there are no colorchanges, but a gradual solution ofthe' solid takes place. After approximately three-fourths of an hoursa heavy lower liquid layer is'formed. The refluxingwith stirringis continued at room temperature for fifteen hours in either case. By this timethe lower liquid layer has changed'to a tacky reddish mass.

Hydrolysz'sond purificationiof the reaction product-containing Compound. I (Methomy) The" reaction product containing -Compound-I (Methoxyl' is: hydrolyzed. by first chillingto. -40 andthen1'500 cc. of 30% aqueous ammonium chloride added slowly and cautiously tO'ithB: chilled materials The rreaction mixtureisallowed itocome. up slowly to room temperature with stirring and isthen stirred until all solid matter has dissolved.

The hydrolysis may be made with aqueous acetic acid, inv which case the reaction product iscooledto-l0 C.. This temperature. is maintained for an additional fifteen minutes: after addition of the acetic acid is complete. In either case the mass is allowed to come to roomtemperature and is filtered- The filtrate separates into two layers; an aqueous layer and an ether layer. The ether layer is separated from the aqueouslayer and washedwith-wa-ter and then with sodium bicarbonate solution to neutralize any residual acetic acid.

A aqueous solution of ammonium acetate may also be used to hydrolyze the reaction product by following the same conditions as when aqueous acetic acid is used.

The neutral reaction product obtained by the hydrolysis is treated to remove therefrom any unreacted methyl ether of the 1,4 chlorohydrin of isoprene which may be present. This may be done by first concentrating the neutralized ether solution of the reaction mass under vacuum and at room temperature and then dissolving the resulting concentrate in about five times its volume of diethylamine or ethyl alcohol and diethylamine and allowing this solution to stand at room temperature for eight to twenty-four hours. This solution is then poured into a large volume of water whereupon liquid oily particles separate out and are extracted with ethyl ether which dissolves the oily material. This ether solution is separated and removed from the aqueous portion of the mix and is then washed with water, with a 5% aqueous solution of acetic acid, with water again, and finally with an aqueous solution of sodium bicarbonate. A small amount of diethylamine is added to the resultant ether solution, and the solution is dried with anhydrous potassium carbonate or other suitable drying agent and is filtered; the filtrate is recovered and concentrated under vacuum at room temperature. This concentrate consists essentially of Compound I (Methoxy) and is distilled under high vacuum. The major portion is distilled at 115-125 C. at mm. and has an index of refraction at 27 C. of 1.5194.

Reduction of Compound I (Memory) to produce Compound [I (Methocsu) Compound I (Methoxy) is dissolved in five to ten times its volume of anhydrous methanol containing 0.0? gram of zinc acetate and 10 cc. of diethylamine per 150 cc. of methanol. To this solution is then added 10 grams of powdered activated charcoal Norite containing one gram of palladium metal uniformly distributed on its surface. This mixture is shaken to thoroughly mix the components and is then shaken under an atmosphere of hydrogen gas at atmospheric pressure. A small amount of hydrogen is absorbed in this step. To this mixture is added thirty grams of calcium carbonate powder containing 0.36 gram of palladium hydroxide uniformly distributed on its surface, and this mixture is again subjected to shaking in an atmosphere of hydrogen at atmospheric pressure. Absorption of hydrogen proceeds rapidly under these conditions. The quantity of hydrogen is measured continuously, as it is being added, by any convenient means. When one mole of hydrogen has been absorbed, this operation is stopped, and the mass is filtered and the filtrate is recovered and consists essentially of a novel compound dissolved in methanol and having the following general formula:

2 Compound II (Methoxy) This methanol solution is poured into a large volume of water which dissolves the methanol and separates the oil therefrom. To this mass is added ethyl ether which dissolves the oil. A

separation into two layers, an ether layer and an- The ether layer is sepasium carbonate or any other suitable drying.

agent. filtered, and the filtrate is recovered and concentrated under vacuum at room temperature. The concentrate is then subjected to high vacuum distillation, preferably at a pressure of .001 or .0001 mm. of mercury pressure, and three fractions are usually separated and collected. One fraction distills at 60-l00 C. at a pressure of 0.001 mm. of mercury and measures about twenty-five grams; a second fraction distills at l00-115 C. at a pressure of 0.001 mm. of mercury and measures about ten grams; and a third fraction which distills at 115-118 C. at a pressure of 0.001 mm. of mercury measures 260 grams. This third fraction has carbon and hydrogen values corresponding to the calculated values of a compound having the formula of Compound H (Methoxy). This third fraction is a golden viscous liquid which shows slight absorption of ultra violet light and has an index of refraction at 26 C. of 1.5099.

Reaction of I-chloro 2 methyl 4-acetory-butens-2 with the double Grz'gnard of a-ethynyl- {i-z'onol to produce Compound I (Acetoaty) Two grams of cuprous bromide were added to the double Grignard of u-ethynyl-eionol, which had been prepared by adding 132 cc..of a 1.585 molar solution of ethyl magnesium bromide in ether to 21.8 grams of a-ethynyl-fi-ionol in 50 cc. of dry ether. The black color of the solution disappeared immediately after the cuprous bromide had been added, and the color of the solution was then light yellow. Eighteen grams of the acetoxy compound, in 20 cc. of ether, were added to the above solution of the double Grignard of a-CthIYllYl-B-lOl'lOl over a period of about ten minutes and within a very short time after the addition was complete a second heavy layer appeared. The solution was stirred under nitrogen for eighteen hours and was then cooled to 20. A saturated solution of ammonium chloride was carefully added, and the solution was then allowed to come up to room temperature. The solution was filtered, washed with water, then alternately with ether and ammonium chloride solutions several times. The solution was again filtered and the other layer was concentrated under vacuum. The residual oil was dissolved in 50 cc. of ethyl alcohol and 50 cc. of diethyl ethanolamine. The solution was allowed to stand at room temperature for a period of two days under nitrogen and in the dark. The dark opaque reaction mixture was poured into several times its volume of brine solution and was extracted with petroleum ether. The petroleum ether layer was washed with dilute acetic acid and then with water and finally with sodium bicarbonate solution. The solution was dried over potassium carbonate and concentrated under vacuum; it was not purified further.

The product of this reaction has the following Compound I (Acetoxy) Reduction of Compound I (Acetoxy) to produce Compound II (Acetoxy) The concentrate from the above reaction was dissolved in 150 cc. of methyl alcohol containing two grams of acetic anhydride. As a catalyst, one gram of catalytic material consisting of palladium or charcoal wherein 10% of the composition was palladium, 2 cc. of water and 10cc. of diethylamine were added to the concentrate. The concentrate plus the catalyst mixture were shaken in the presence of hydrogen until an amount of hydrogen slightly in excess of the theoretical amount required to reduce an acetylenic bond to an ethylenic bond had .been absorbed. The catalyst was then filtered ofif, and the resulting filtrate was poured into brine. This mixture was extracted several times with ether, washed well with water, and the ether solution was dried over potassium carbonate. The ether solution was filtered, concentrated under vacuum, and finally distilled at 10 mm. Three fractions were taken. The first fraction came over at 60105 and had a refractive index of n =1.5128; the second fraction came over at 105-110 and had a refractive index of n =1.52'78 and the third fraction came over at 1l0-l50 and had a refractive index of n =1.5390. The third fraction represents the reduced product and has the following formula;

Compound II (Acetoxy) The following exemplary material is given in order to illustrate the practice of the invention in one of its specific embodiments, and it is not intended that the examples are to be construed in a limiting sense.

EXAMPLE I Catalytic dehydration of Compound II (M ethoazy) Ten grams of distilled Compound II (Methoxy) dissolved in 100 cc. of dry benzene, were added to 20 cc. of phenylisocyanate and 3 mg. of anhydrous ferric chloride were added to the mixture and the whole was refluxed for two hours. The benzene and any excess, unreacted isocyanate were distilled off under vacuum. The residual pasty mass was extracted with two 100 cc. portions of petroleum ether, boiling at 30-60 0., and the petroleum ether solution was filtered to remove any insoluble diphenylurea. The petroleum ether filtrate was washed with water and dried over anhydrous potassium carbonate. The petroleum ether was distilled under high vacuum, and the residue was distilled. The major portion distilled at l-115 C. at 10- mm. and had an index of refraction at 25 C. of 1.575.

EXAMPLE ]I Catalytic dehydration of Compound II (Acetoxy) Ten grams of distilled Compound II (Acetoxy) dissolved in 100 cc. of dry benzene, were added to cc. of phenylisocyanate, followed by the addition of 3 mg. of anhydrous ferric chloride. This mixture was refluxed for two hours. The benzene and excess of phenylisocyanate were distilled ofi under vacuum and the residual pasty mass was extracted with two 100 cc. portions of petrotive index of n =1.5692.

10 leum ether, boiling at 30-60" C. and filtered to remove any insoluble diphenylurea. The petroleum ether filtrate was washed with water and dried over anhydrous potassium carbonate. The petroleum ether was distilled and the residue was subjected to distillation under high vacuum; the distillate was contaminated with diphenylurea. The crude product was dissolved in 50 cc. of petroleum ether and again filtered from insoluble diphenylurea. The petroleum ether was removed by distillationand the residue was distilled under high vacuum. A distillate boiling at 105-120C. at 10- mm. was obtained which was free from diphenylurea and which had a refrac- Ihe yield of distilled product was 14.5 grams.

EXAMPLE III Catalytic dehydration of Compound II (M ethoxy) Three mg. of anhydrous magnesium iodide were added to a reaction mixture prepared by adding 10 grams of distilled Compound II (Methoxy), dissolved in cc. of dry benzene to 20 cc. of phenylisocyanate; the whole was refluxed for two hours. The benzene and any unreacted phenylisocyanate were distilled off under vacuum. The residue was extracted with two 100 cc. portions of petroleum ether, boiling at 30-60 C., and this solution was filtered to remove insoluble diphenylurea. The petroleum ether was removed by distillation under high vacuum, and the residue, containing the dehydration product of Compound II (Methoxy), was distilled under high vacuum; the major portion distilled at 115 C. at 10- mm. and had an index of refraction at 25 of 1.575.

EXAMPLE IV Catalytic dehydration of Compound II (M ethoxy) Three mg. of anhydrous cadmium iodide were added to a reaction mixture prepared by adding- 10 grams of distilled Compound II (Methoxy), dissolved in 100 cc. of dry benzene to 20 cc. of phenylisocyanate; the whole was refluxed for two hours. The benzene and any unreacted phenylisocyanate were distilled off under vacuum. The residue was extracted with two 100 cc. portions of petroleum ether, boiling at 30-60 0., and this solution was filtered to remove insoluble diphenylurea. The petroleum ether was removed by distillation under high vacuum, and the residue, containing the dehydration product of Compound II (Methoxy), was distilled under high vacuum; the major portion distilled at 105-115" C. at 10* mm. and had an index of refraction at 25 of 1.575.

What is claimed is:

1. A process for dehydrating a compound with the following general formula:

wherein X is selected from the group consisting of OR and 0y]R and R. is a hydrocarbon radical; which comprises reacting the said compound with phenyl isocyanate in the presence of a catalyst selected from the group consisting of anhydrous inorganic salts of metals of group II and anhydrous inorganic ferric salts.

A process for dehydrating a compound having the following formula:

CH CH3 which comprises reacting the said compound with phenyl isocyanate in the presence of a catalyst selected from the group consisting of anhydrous inorganic salts of metals of group II and anhydrous inorganic ferric salts.

3. A process for dehydrating a compound with the following general formula:

CH: CH:

which comprises reacting the said compound with phenyl isocyanate in the presence of a catalyst 6. A process according to claim 1 in which thecatalyst is ferric thiocyanate.

GEORGE KARMAS.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Name Date Hearne Apr. 1'7, 1945 OTHER REFERENCES Oroshnik, Jour. Am. Chem. Soc., vol. 67, 1628 (1945).

Karrer et al., Helv. Chem. Acta., vol. 29, 704- 708 (1946).

Number 2,373,956

Certificate of Correction Patent No. 2,574,484 November 13, 1951 GEORGE KARMAS It is hereby certified that error appears in the printed specification of the above numbered patent requiring correction as follows:

Column 2, line 16, for that portion of the equation reading for that portion of column 6, line 22, for read EUMgBr; line 26,

line 50, for espectially read especially,- column 3, line 52, the equation reading CH OCH read 0H 00H that portion of the equation reading CCMgBr for fi-ional read fl-ionol and that the said Letters Patent should be read as corrected above, so that the same may conform to the record of the case in the Patent Office.

Signed and sealed this 12th day of February, A. D. 1952.

THOMAS F. MURPHY,

Assistant Gommim'oner of Patenta. 

1. A PROCESS FOR DEHYDRATING A COMPOUND WITH THE FOLLOWING GENERAL FORMULA: 